The present invention relates to a phototherapy based method for treating pathogens and to a pharmaceutical composition for effecting same. More particularly, the present invention relates to a laser based method and a pharmaceutical composition for treating nail and skin associated pathogens, such as fungi, yeast, bacteria, and viruses which cause nail and skin infections.
The nails, which are thin horny plates consisting of modified epidermis growing on the upper side of the end of the digits (fingers or toes), serve many useful functions, such as protecting the digits, enhancing fine touch, and increasing tactile sensitivity.
The nails are essential for picking up small objects and for performing fine activities such as fastening a button. The nails provide an excellent tool for scratching and can be used as both offensive and defensive weapons. Furthermore, being external and exposed, the nails serve as an important aesthetic attribute.
Thus, any condition that adversely affects one or more of the nails may have deleterious consequences, affecting not only a person's ability to perform some delicate and other daily tasks, but potentially adversely affecting his or her quality of life in a broader sense.
Onychomycosis is a general infection of the nail unit caused by fungal microorganisms such as dermatophytes, yeasts, and nondermatophyte molds. The term tinea unguium refers to dermatophytic infection of a nail unit.
Onychomycosis may affect toe nails as well as fingernails, and may lead to onycholysis (separation of nail plate from the nail bed), subungal debris or hyperkeratosis, discoloration of the nail plate, partial or complete destruction of the nail plate, and thickening of the nail plate, leading to both functional and aesthetic problems [Farmer et al. (1996) Guidelines of care for superficial mycotic infections of the skin: onychomycosis. J. Am. Acad. Dermatol. 34:116-121].
Onychomycosis occurs worldwide and its incidence has been steadily increasing [Daniel (1991) The diagnosis of nail fungal infection. Arch. Dermatol. 127:1566-1567]. Nail disorders comprise approximately 10% of all dermatologic conditions [Farmer et al. (1996) Guidelines of care for nail disorders. J. Am. Acad. Dermatol. 34:329-533]. Up to 50% of all nail disorders are caused by fungal infections [Achten and Wanet-Rouard (1978) Onychomycosis in the laboratory. Mykosen 23:125-127; and Andre and Achten (1987) Onychomycosis. Int. J. Dermatol. 26:481-490].
Onychomycosis is often considered an age-related infection. In some populations, as many as 15% to 20% or more of individuals between the ages of 40 and 60 years of age are affected by onychomycosis [Zaias (1985) Onychomycosis. In: Daniel C. R. III, Ed. Dermatologic clinics. Philadelphia: WB Saunders Co. pp. 445-460].
In 1989, Rosenbach and Schneider conducted a comprehensive study to evaluate the overall costs of onychomycosis in the Medicare population (e.g., &gt;65 years of age) of the U.S. [Scher (1996) Onychomycosis: A significant medical disorder. J. Am. Acad. Dermatol. 35 (supp.):2-5]. The results revealed that, during a twelve month period, between 1989 and 1990, a total of 662,000 patients had made 1,300,000 visits to a physician because of a primary complaint of onychomycosis. At the time this study was conducted the costs associated with these visits exceeded $43 million.
Various factors are considered to cause the reported increase in onychomycosis cases. These include (i) growing population of elderly people; (ii) spread of HIV infections (AIDS), which affect immune capabilities; (iii) increased use of therapeutic interventions resulting in immunosuppression; (iv) "health craze", (v) use of occlusive clothing and shoes; (vi) extensive and prolonged sweating associated with vigorous physical activities such as tennis, paddle ball, etc.; and (vii) communal bathing facilities.
People affected with onychomycosis may suffer various physiological and psychological consequences.
The physiological consequences associated with onychomycosis may include (i) limitations in mobility due to pain; (ii) reduced peripheral circulation and, as a result, slow healing thereat; (iii) exacerbation of the diabetic foot; (iv) recurrent thrombophlebitis and cellulitis; and (v) creation of a fungal reservoir, which may trigger urticaria; bacterial infections; pain; and dermatophytic reactions.
The psychological consequences associated with onychomycosis may include (i) embarrassment; (ii) low self-consciousness; (iii) loss of self-esteem; (iv) loss of self-confidence; (v) anxiety; (vi) depression contagion; (vii) social effects; (viii) impaired relationships; and in some cases even (ix) avoidance of intimacy; all depending, of course, on the specific affected individual and its psychological profile. Individuals of the females gender are probably more susceptible to the psychological consequences associated with onychomycosis, especially of the fingernails.
With reference to FIG. 1, presented is a human toe nail having a plate 10 a nail bed 12 and a matrix or growth origin 14. There are four major types of fungal nail infections: distal subungual onychomycosis (DSO), proximal subungual onychomycosis (PSO), white superficial onychomycosis (SFO) and Candida onychomycosis (CAN). The affected regions are marked in FIG. 1. Each of the four types of fungal nail infections is differentiated on the basis of the pattern of fungal invasion into the nail plate and by the causative pathogen.
In the most common form of onychomycosis, distal subungual, the fungus (typically Trichophyton rubrum) invades distally in the area of the hyponychium.
In proximal subungual onychomycosis, the fungus (again, typically T. rubrum) invades under the cuticle and spreads distally from the proximal nail bed region.
In white superficial onychomycosis, the fungus (typically T. mentagrophytes or certain molds, such as various Fusarium sp.) directly invades the nail plate.
Candida onychomycosis occurs in patients with chronic mucocutaneous candidiasis and involves invasion of the entire nail plate by Candida organisms (typically C. albicans)
There are three major groups of fungi that cause onychomycosis. These are dermatophytes, yeasts, and non-dermatophyte molds. However, dermatophytes remain, by far, the most common pathogens associated with onychomycosis. The largest study in the field [Summerbell et al. (1989) Onychomycosis, tinea pedis and tinea manuum caused by nondermatophytic filamentous fungi. Mycoses 32:609-619] revealed that in more than 3,000 studied nails, 91% of fungal infections were caused by dermatophytes, 6% by Candida sp.; and 3% by nondermatophyte molds (primarily Scopulaiopsis brevicaulis). In the dermatophyte group, in 70% of the cases studied the causative pathogen was Trichophyton rubrum, in 20% T mentagrophytes and in 10% other pathogens [Brener (1996) Nail and hair. Dyonon, Tel Aviv University, p. 43].
Elewski [Elewski (1996) Diagnostic techniques for confirming onychomycosis. J. Am. Acad. Dermatol. 35 (supp.):6-9] findings are similar, wherein 90% of fungal nail infections studied were found to be caused by dermatophytes; 7% by Candida sp.; and 3% by nondermatophyte molds.
A study by Clayton in the United Kingdom [Clayton (1992) Clinical and mycological diagnostic aspects of onychomycosis and dermatomycosis. Clin. Exp. Dermatol. 17 (supp. 1):37-40] showed that, of 699 specimens, 81% of nail infections were caused by dermatophytes, 17% by yeasts, and 2% by nondermatophyte molds.
The common dermatophyte species associated with onychomycosis, their associated pathogenicity, growth rates and colonies morphology when grown in culture are listed below. The morphology of culture grown colonies of a studied pathogen, in many cases, serves as a diagnostic tool.
Trichophyton rubrum
Pathogenicity: Typically infects the skin and nails. Rarely infects the beard, hair, or scalp. T. rubrum is presently the most common dermatophyte to infect human beings.
Rate of growth: Slow. Maturation within 14 days.
Morphology and color of colony: Surface of colony is granular or fluffy, white to buff. Reverse (i.e., viewed from underneath) is deep red or purplish, occasionally brown, yellow, orange, or even colorless. Pigment production is best seen when colonies are grown in culture in presence of cornmeal or potato dextrose containing agar. The pigment responsible for the color of Trichophyton rubrum colonies is carotene. For action during arthoroconidia formation see Rippon (1982) "Medical Mycology", W. B. Saunders Company. p. 213. The pigment is slow in developing. The color is yellow initially, developing through a Melanoid-green, and finally becoming red. Several pigments are formed by Trichophyton rubrum at different times. A black melanin like pigment is sometimes produced. This is the var. nigricans [Rippon (1988) "Medical Mycology", W. B. Saunders Company. p. 257].
Trichophyton mentagrophytes
Pathogenicity: Invades all parts of the body surface, including hair and nails. T. mentagrophytes is the most common causative pathogen associated with athlete's foot.
Rate of growth: Moderate. Maturation within 7-10 days.
Morphology and color of colony: Varies greatly. Surface may be buff and powdery or white and downy. May develop a pinkish or yellowish color. The powdery form exhibits concentric and radial folds. Colonies rapidly develop a dense fluff with little or no conidiation. Reverse is usually brownish tan but may be colorless, yellow, or red.
Epidermophyton floccosum
Pathogenicity: Produces infection in skin and nails. Does not infect hair.
Rate of growth: Moderate. Maturation within 10 days.
Morphology and color of colony: Surface is brownish-yellow to olive-gray or khaki. At first it is lumpy and sparse and then folded in center and grooved radially, becoming velvety. After several weeks, fluffy white sterile mycelium covers the colony. Reverse is orange to brownish, sometimes with a thin yellow border.
Trichophyton tonsurans
Pathogenicity: The principle etiologic agent of scalp ringworm in the United States. Also infects the skin and nails.
Rate of growth: Moderately slow. Maturation within 12 days.
Morphology and color of colony: Highly variable. Surface may be white, gray, yellow, rose, or brown. Surface is usually suedelike, with many radial or concentric folds. Reverse is usually reddish-brown (pigment may diffuse into the medium). Sometimes it is yellow or colorless.
Trichophyton violaceum
Pathogenicity: Infects the scalp, hair, skin, and nails.
Rate of growth: Slow. Maturation within 14-21 days.
Morphology and color of colony: Original cultures are waxy, wrinkled, heaped, and characterized by a deep purplish-red color. Subcultures are more downy, and they decrease in color. Reverse color is lavender to purple.
Trichophyton schoenleini
Pathogenicity: Causes favus, a chronic, scarring scalp infection that results in permanent hair loss. Sometimes infects the nails and skin.
Rate of growth: Slow. Maturation within 15 days.
Morphology and color of colony: Colony is whitish, waxy, or slightly downy; heaped or folded; and sometimes yeastlike. Growth is often submerged in the agar. Reverse is colorless or yellowish orange to tan.
Trichophyton verrucosum
Pathogenicity: Infects scalp, beard, nails, and skin of various parts of the body. Usually contracted from cattle.
Rate of growth: Slow. Maturation within 14-21 days. Unlike other dermatophytes, this fungus grows best at 37.degree. C.
Morphology and color of colony: Usually small, heaped and buttonlike but sometimes flat. Texture skinlike, waxy, or slightly downy. Usually white, but can be gray or yellow. Reverse varies from nonpigmented to yellow.
Microsporum ferrugineum
Pathogenicity: Primarily causes ringworm of the scalp (tinea capitis) in children. Also known to infect the skin and nails.
Rate of growth: Slow. Maturation within 12-20 days.
Morphology and color of colony: Surface is usually yellow to rusty orange, smooth, waxy, heaped; may be flatter and develop a white velvety fuzz. Reverse is creamish to brownish. During repeated subculturing, the colonies often lose their pigment.
Microsporum canis var. canis
Pathogenicity: Causes infections of scalp and skin. Most prevalent in children. Has occasionally been reported to cause nail infection. Most infections in humans are acquired from infected dogs or cats.
Rate of growth: Moderate. Maturation within 6-10 days.
Morphology and color of colony: Surface is whitish, coarsely fluffy, with yellow pigment at the periphery and closely spaced radial grooves. Reverse is deep yellow and turns brownish-yellow with age.
The common Candida species associated with onychomycosis, their associated pathogenicity, growth rates and colonies morphology in culture are listed below.
Candida albicans
Pathogenicity: Most common cause of candidiasis (also known as candidosis), which is an acute, subacute, or chronic infection involving any part of the body. This organism may also be found as normal flora in the skin, mouth, vaginal mucous membranes, and stools.
Rate of growth: Rapid. Maturation within 3 days.
Morphology and color of colony: Cream colored, pasty, smooth.
Candida tropicalis
Pathogenicity: As is the case for many species of Candida and other yeasts, C. tropicalis is known to cause infection, especially in immunocompromised, predisposed patients. It is also found without evidence of a disease.
Rate of growth: Rapid. Maturation within 3 days.
Morphology and color of colony: Creamy with mycelial fringe.
Candida parapsilosis
Pathogenicity; This species has been known to cause infections in particularly susceptible individuals. It is a relatively frequent cause of candidal endocarditis.
Rate of growth: Rapid. Maturation within 3 days.
Morphology and color of colony: Creamy, sometimes developing a lacy appearance.
The common Mold species associated with onychomycosis, their associated pathogenicity, growth rates and colonies morphology when grown in culture are listed below.
Scopulariopsis spp.
Pathogenicity: Commonly considered a contaminant, but is known to infect the nails (usually toe nail) and is rarely associated with infection of soft tissue, bone, and lungs in immunocompromised patients.
Rate of growth: Rapid. Maturation within 5 days.
Morphology and color of colony: Surface is at first white and glamorous and then usually becomes powdery light brown with a light tan periphery. Some rarely encountered species may be very dark. Reverse is tan with brownish center.
Fusarium spp.
Pathogenicity: Commonly considered a contaminant, but known to be a relatively frequent agent of mycotic eye infections. It is occasionally involved in myvetoma, sinusitis, skin and nail infections, and disseminated systemic infections in severely debilitated hosts. Disease has also been reported in individuals after ingestion of food prepared from grains that have been overgrown by toxin producing species.
Rate of growth: Rapid. Maturation within 4 days.
Morphology and color of colony: At first the colony is white and cottony, but it often quickly develops a pink or violet center with a lighter periphery. Some species remain white or become tan. Reverse is light in color.
Pigments produced by various molds, fungi and bacteria in different developmental stages and as a response to an inducer (e.g., nutrient, radiation, temperature, etc.) include, but are not limited to, aspergillin, aurantin, aurofusarin, boletol, carotennoids, catenarin, chrysogenin, citrinin, citromycetin, cynodontin, erythroglaucin, flavoglaucin, fulvic acid, helminthosporin, monascoflavin, monascorubin, ochracin, ousporin, pheonicin, physcion, ravenelin, rubrofusarin, melanin, and tritsporin [Salle (1948) "Fundamental Principles of Bacteriology", McGraw-Hill book company, New York].
The colors associated with cultured colonies is induced by various growth conditions, including, but not limited to nutrients, temperature and irradiation. Since when grow as parasites the above fungi typically do not develop colors, diagnostic techniques for confirming onychomycosis were developed. These include direct microscopy, fungal culturing (as described), nail histopathology, immunohistochemistry and flow cytometry.
The treatment for onychomycosis has been disappointing because of its duration, poor response rate, side effects and high incidence of recurrence. Treatment for onychomycosis may be divided to nonpharmacological approaches, topical antifungal agents and oral therapy.
Nonpharmacological approaches: Various nonpharmacological approaches are used to manage nail fungal infections, including buffing or filing of the nails, nail avulsion or debridement, and the use of surgery and/or various chemicals and solutions to remove the nail plate. These procedures are uncomfortable and probably do not reduce the likelihood of relapse. In addition, they may permanently alter the shape of the nail unit and lead to persistent non attachment of the nail plate to the nail bed (onycholysis) and increase the likelihood of ingrown nails. Chemical removal of dystrophic nails should be reserved for patients with onychogryphosis or very thick nails, or for painful nails in patients who cannot undergo surgery. Unfortunately ,these methods do not "cure" the infection, but only keep the worst aspects of the disease under some control.
Topical antifungal agents: Numerous topical antifungal agents (creams, lotions, solutions, powders and sprays) are used for the empirical management of onychomycosis. It is widely agreed that these preparations are largely ineffective, even when used in conjunction with nail avulsion. The experience with the newer topical solutions, such as nail lacquers (e.g., amorolfine) is inconclusive.
Some traditional topical antifungal agents are used to treat dermatophyte infections. These include azoles (ketoconazole, clotrimazole, sulconazole, oxiconazole and econazole) with or without urea, Whitefield's ointment, potassium permanganate, ciclopirox olamine, amorolfine, allylamines (naftifine, terbinafine), organic acids (salicylic, undecylenic), halogenated phenolic esters (haloprogin), thiocarbamate derivatives (tolnaftate), and polyenes (nystatin) which are not effective against dermatophytes.
A combination of a nonpharmacologic approach and a topical antifungal agents is disclosed in SU 1801519 A to Abramovitch et al., wherein following the removal of the onychomycosial nail plate, the nail bed is treated by a fungicidal preparation and further by recurrent (25-30 sessions) irradiations of the nail bed by a low density (1-2 mW/cm.sup.2) red laser beam.
Oral therapy: The two oral antifungal drugs that have traditionally comprised the mainstay of the treatment of onychomycosis are griseofulvin and ketoconazole. These two oral anti fungal agents have been used for the treatment of onychomycosis for almost half a century. One of the major limitations of treatment with either griseofulvin or ketoconazole is the long duration of therapy required. In addition, the clinical and mycological cure rates are low, and there is a greater than 75% probability that the patient will relapse within two years. The potential for significant side effects is another problem, particularly with ketoconazole.
The new generation orally administered antifungal agents are fluconazole and itraconazole. Itraconazol adverse effects include nausea, abdominal pain, vomiting, diarrhea, anorexia, headaches, dizziness, rash, pruritus, fatigue, fever, elevation of liver test and hepatic injury. Fluconazole adverse effects include nausea, abdominal pain, vomiting, diarrhea, elevation of liver test and hepatic injury.
Orally administered allylamines, such as terbinafine and naftifine, adverse effects include gastrointestinal irritation, dyspepsia, stomachache, gastritis, fullness, nausea, vomiting, diarrhea, hepatobiuary dysfunction including hepatitis, skin reactions, urticaria rash. When administered it becomes essential to monitor liver functions.
When orally administering any of these drugs, liver function monitoring becomes essential [Gupta et al. (1994) Continuing Medical Education Antigungal Agents: An Overview. Part II, 30:911-33].
Properties of an "ideal" oral antifungal agent most suitable for the treatment of onychomycosis would include favorable nail kinetics, good incorporation into the nail matrix, adequate diffusion through the nail bed, high clinical cure rate, high mycological cure rate, low incidence of relapse, effective when used for short-term therapy, low incidence of side effects, fewer drug interactions with other drugs or food, etc., and cost effectiveness.
Unfortunately, non of the oral anti fungal agents, neither the traditional nor the new generation drugs is ideal because of the potential for significant side effects, drug interaction, high incidence of relapse, long term therapy and high cost.
Light sources, e.g., lasers, xenon lamps, etc., are commonplace in medicine for different applications. For example, lasers are used in surgery for both cutting and cauterization. Other applications use the property of absorption of light energy in order to transfer it to the tissue. One common usage of lasers involve phototherapy, particularly the treatment of tumors of different types by burning. Enhancing light absorption of the tumor enables the efficient transfer of laser energy to it, its heating and finally, its destruction.
In general, special substances that have an efficient absorption coefficient of the light wavelength employed are introduced by various methods into the tissue to be treated. Illuminating (irradiating) the treated area of skin or tissue with an energetic light beam, transfers some of the light energy, preferably most of it, to the light absorbent substance. The substance, which absorbs energy faster than it is lost, is thus heated. Depending on the absorbent substance, the tissue, and the light source properties, the nearby area is also heated. Using the right parameters of light intensity, duration and wavelength with a suitable choice for a light absorber, one can create the desired heating and curing effects in the tissue.
U.S. Pat. Nos. 5,226,907 and 5,425,728 to Tankovich discloses a device and process for the permanent removal of unwanted human hair. Hair is contaminated with a substance which strongly absorbs a specific wavelength of light. The skin is then illuminated by a laser producing light at the specified wavelength and at a sufficient intensity and duration to kill the follicles or the skin tissue feeding the hair. There is however no discussion of pathogens treatment using laser technology.
There is thus a widely recognized need for, and it would be highly advantageous to have, a phototherapy method for treating skin and nail pathogens and a pharmaceutical composition to effect same.